The showdown pitted lawmakers from coal-producing and manufacturing states such as Kentucky and Indiana against those in such states as Tennessee that are downwind of the pollution created by plants in neighboring states. The 41-56 vote fell largely along party lines.

Lawmakers offered impassioned debate on Paul's measure to overturn the federal Cross-State Air Pollution Rule, which requires 27 states in the eastern part of the country to curb smog and other pollution.

"I think we can have a clean environment and jobs," Paul said during the Senate floor debate Thursday. "But not if we let this administration continue to pass job-killing regulations."

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He was supported by fellow Kentucky lawmaker and Senate Minority Leader Mitch McConnell, who voted for the measure, as well as such conservative groups as FreedomWorks, a political organization founded by former U.S. House Majority Leader Dick Armey.

The refrain to decrease federal regulations is one Republicans in the Kentucky congressional delegation and their GOP brethren in both chambers have echoed all year. In Kentucky, where coal mining has been the lifeblood of many rural communities, lawmakers say the Obama administration's push for increased regulations on carbon-based pollution feels like an assault.

"The Obama Administration's regulatory power grab is costing Americans — and the EPA's overzealous, job-killing approach to environmental protection is too. I am pro-clean air. I am pro-clean water. I am pro-jobs. Repealing this rule would have afforded us all three of those things," Paul said after the vote.

Such Republican complaints about the Obama administration's regulations have colored debates this year on everything from issuing mining permits to issuing new regulations on greenhouse gases. GOP lawmakers from Kentucky and other mining and manufacturing states have battled the administration's efforts through legislation designed to weaken the Environmental Protection Agency's regulatory authority and by attacking agency director Lisa Jackson.

President Barack Obama had threatened to veto Paul's measure and the White House Office of Management and Budget issue a statement earlier this week saying Paul's measure "would cause substantial harm to public health and undermine our nation's longstanding commitment to clean up pollution from power plants."

It estimates $120 billion to $280 billion in annual health benefits — from lives saved and avoided medical costs. That compares to costs of about $2.4 billion a year — much of it already being spent as a result of an earlier version of the regulation.

Thursday's debate was a bit different from this year's earlier environmental regulatory policy fights in Congress, in that some Southern Republicans joined in the fray and aligned themselves with Democrats seeking to defeat Paul's measure. Tennessee Republican Sen. Lamar Alexander blasted what he called Paul's "political message."

"And what kind of message is it that we favor dirty air blowing from Kentucky into Tennessee?" Alexander said. "Nine million people a year come to see the Great Smoky Mountains, not the Great Smoggy Mountains."

Environmental and health groups cheered Thursday's vote.

"This vote is a clear rejection of efforts to block commonsense clean air health protections," Paul Billings, vice president of national policy and advocacy for the American Lung Association said in a statement. "With six Republican Senators and 50 of their Democratic colleagues voting against this outrageous attack on public health, we are encouraged to see a growing number of legislators on both sides of the aisle recognizing the importance of putting clean air ahead of corporate interests."

(Renee Schoof contributed to this report. Also contributing was Maha Mussadaq, a reporter at The Express Tribune Islamabad, Pakistan. Mussadaq is reporting for The McClatchy Washington Bureau in partnership with the International Center for Journalists. The program is funded by the U.S. State Department).